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@ARTICLE{Ovesen:276822,
author = {Ovesen, Peter Lund and Juul-Madsen, Kristian and Telugu,
Narasimha S and Schmidt, Vanessa and Frahm, Silke and
Radbruch, Helena and Louth, Emma Louise and Korshøj, Anders
Rosendal and Heppner, Frank L and Diecke, Sebastian and
Kettenmann, Helmut and Willnow, Thomas E},
title = {{A}lzheimer's {D}isease {R}isk {G}ene {SORL}1 {P}romotes
{R}eceptiveness of {H}uman {M}icroglia to
{P}ro-{I}nflammatory {S}timuli.},
journal = {Glia},
volume = {73},
number = {4},
issn = {0894-1491},
address = {Bognor Regis [u.a.]},
publisher = {Wiley-Liss},
reportid = {DZNE-2025-00335},
pages = {857 - 872},
year = {2025},
abstract = {Sorting protein-related receptor containing class A repeats
(SORLA) is an intracellular trafficking receptor encoded by
the Alzheimer's disease (AD) gene SORL1 (sortilin-related
receptor 1). Recent findings argue that altered expression
in microglia may underlie the genome-wide risk of AD seen
with some SORL1 gene variants, however, the functional
significance of the receptor in microglia remains poorly
explained. Using unbiased omics and targeted functional
analyses in iPSC-based human microglia, we identified a
crucial role for SORLA in sensitizing microglia to
pro-inflammatory stimuli. We show that SORLA acts as a
sorting factor for the pattern recognition receptor CD14,
directing CD14 exposure on the cell surface and priming
microglia to stimulation by pro-inflammatory factors. Loss
of SORLA in gene-targeted microglia impairs proper CD14
sorting and blunts pro-inflammatory responses. Our studies
indicate an important role for SORLA in shaping the
inflammatory brain milieu, a biological process important to
local immune responses in AD.},
keywords = {Humans / Microglia: metabolism / Alzheimer Disease:
genetics / Alzheimer Disease: metabolism / Alzheimer
Disease: pathology / LDL-Receptor Related Proteins: genetics
/ LDL-Receptor Related Proteins: metabolism / Membrane
Transport Proteins: genetics / Membrane Transport Proteins:
metabolism / Lipopolysaccharide Receptors: metabolism /
Lipopolysaccharide Receptors: genetics / Induced Pluripotent
Stem Cells: metabolism / Inflammation: metabolism /
Inflammation: genetics / Alzheimer's disease (Other) / SORLA
(Other) / VPS10P domain receptors (Other) / brain
inflammation (Other) / microglia (Other) / SORL1 protein,
human (NLM Chemicals) / LDL-Receptor Related Proteins (NLM
Chemicals) / Membrane Transport Proteins (NLM Chemicals) /
Lipopolysaccharide Receptors (NLM Chemicals) / CD14 protein,
human (NLM Chemicals)},
cin = {AG Heppner},
ddc = {610},
cid = {I:(DE-2719)1810007},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39688327},
pmc = {pmc:PMC11845846},
doi = {10.1002/glia.24659},
url = {https://pub.dzne.de/record/276822},
}